The present invention concerns a new process for the separation of mixtures of 4-androsten-3,17-dione and 1,4-androstadien-3,17-dione, resulting upon microbiological sterol-side chain decomposition.
4-androsten-3,17-dione and 1,4-androstadien-3,17-dione are important starting materials for the synthesis of androstan- and pregnan-derivatives, as well as estratrienes.
With the technical use of microbiological sterol side-chain decomposition, 4-androsten-3,17-dione and 1,4-androstadien-3,17-dione are easily accessible products for the synthesis of steroids.
4-androsten-3,17-dione is the starting material for the synthesis of
androstan derivatives such as testosterone, methyltestosterone, spironolactone, among others,
pregnan derivatives such as progesterone, 17.alpha.-hydroxyprogesterone, hydrocortisone, among others.
1,4-androstadien-3,17-dione is easily converted into estratriene derivatives by aromatization reactions. The 1,4-androstadien-3,17-dione accessible in this manner is more economically favorable for the synthesis of estratrienes than the production of these products through total synthesis.
According to processes described in the literature, involving microbiological sterol-side chain decomposition, as a rule mixtures of 4-androsten-3,17-dione and 1,4-androstadien-3,17-dione of different composition, in addition to small amounts of other decomposition products, are obtained (AP No. 130 789 Upjohn, DE-AS No. 2 703 645 Upjohn). The yields amount to an average 50% up to 80% of the 4-androsten-3,17-dione/1,4-androstadien-3,17-dione mixture.
Through the use of different organisms for the sterol-side chain decomposition, the microbiological decomposition processes can be so controlled that not only 4-androsten-3,17-dione but also 1,4-androstadien-3,17-dione are produced as main products, and the other mixture components are produced in order of magnitude of about 5 up to 25%.
For the separation of such a mixture, different processes are described in the literature. Thus, the separation and purification of 1,4-androstadien-3,17-dione from the steroid mixture of 1,4-androstadien-3,17-dione and cholesterin, isolated by microbiological sterol-side chain decomposition, follow through treatment with A-coal and subsequent column chromatography (JA No. 7 514 958, Tayoko Co., Ltd.).
According to another process (JA No. 78 127 454, Mitsubishi), the 3-keto-1,4-diene-steroid is converted through treatment with K-t-butylate into the corresponding 3-keto-1,5-diene-derivative, and subsequent hydrogenation with a Rh/c-catalyst in a heterogeneous system into 5-androsten-3,17-dione. The yields in this two-stage process amount to about 50-60%.
A further process (JA No. 78 130 650, Mitsubishi) provides for the direct hydrogenation of 3-keto-1,4-diene-steroid with rhodium-tris-(triphenylphosphine)chloride-catalysts in homogeneous systems. The yield of 3-keto-4-an-steroids amounts to about 90%, relative to the 3-keto-4en-steroid contained in the mixture.
The separation of the steroid from this steroid-catalyst mixture requires great expenditures, which are connected with further losses of substance, the total yield lowering to about 80% of the obtained decomposition product (JA No. 78 127 452, Mitsubishi; No. 78 130 649, Mitsubishi). A further disadvantage of these methods is that the selectivity of the catalysts in these reactions is not sufficient, and up to 5% completely hydrogenated 5.alpha.-androstan-3,17-dione are obtained in the reaction mixture (JA No. 78 127 452, Mitsubishi). It has also already been suggested to selectively reduce the 1,4-androstadiene-3,17-dione present in the mixture into 4-androsten-3,17-dione, through use of a second microbiological stage (WP No. 137 361).
All of the previously suggested processes require, however, high additional expenditures, which are connected moreover with further decreases in yield.
Since both products, 1,4-androstadien-3,17-dione, particularly though 4-androsten-3,17-dione, are required for steroid synthesis, according to the methods previously described in the literature, different processes for the production of these products are necessary, whereby the separation of the second, androstan derivative, contained in the produced mixture, for technical use is solved completely unsatisfactorily.